Polymer matrices designed for controlled release of bioactive compounds can be non-resorbable or resorbable. In general, resorbable means biologically degradable in the body by erosion from the surface of breakdown from within. The mechanism can involve either a chemical reaction, such as hydrolysis, or dissolution. Non-resorbable polymers, such as polymethylmethacrylate, have been used for antibiotic delivery. These materials suffer from the disadvantage that they must be retrieved, which involves a second intervention and entails the risk of infection (H W Bucholz, et al., (1970) Chiburg, 43, 446).1 1This publication as well as other publications cited hereinbelow are expressly incorporated in their entirety into this application.
Preparation of oxidized dextran is described in U.S. Pat. No. 5,783,214 to Royer. Oxidized hyaluronic acid has been used in reactions with amino polysaccharides to form complexes as described in U.S. Pat. No. 6,305,585 to Spiro et al; however, the disclosed method is less convenient and more expensive compared to the system described herein. Also, the cross-linking conditions require uncharged amino groups, which eliminates many active ingredients, as they would react with the polymer. The gel described in U.S. Pat. No. 6,305,585 is prepared in bulk by reacting two polymer solutions at alkaline pH. Lee et al, Macromolecules, 33, 97-101 (2001), have described a structural biomaterial made of poly(guluronate), which involves an oxidized polymer isolated from alginic acid. The starting material is not commercially available, is expensive to produce, and has not been FDA-approved for medicinal use. The production of this biomaterial occurs at high pH that would involve reaction of amino groups in proteins or of other medicinal compounds.
Another polysaccharide that finds application in medicine is carboxymethylcellulose used in drug formulation and also the production of anti-adhesion compositions for post-surgical treatment following several types of procedures (Schwartz H E and Blackmore J M, U.S. Pat. Nos. 6,017,301, 6,133,325, and 6,034,140; Miller M E, Cortese, S M, Schwartz, H E, and Oppelt, W G, U.S. Pat. No. 6,566,345; Liu, L S and Berg, R, U.S. Pat. No. 6,923,961; Schwartz, H W, Blackmore, J M, Cortese, S M, and Oppelt, W G, U.S. Pat. No. 6,869,938). These formulations involve the non-covalent aggregation of carboxylated polysaccharides with polyethyleneglycols.
Hyaluronic acid has been used as a biomaterial for a number of applications. Gertzman and Sunwoo have employed the sodium salt of high molecular weight hyaluronic acid to deliver demineralized bone matrix (U.S. Pat. Nos. 7,019,192; 6,911,212; 6,458,375; and 6,326,018). The material used is a solution and does not involve chemical cross-linking as described herein. The covalent cross-linking provides for gel stability and retards migration of the bioactive agent. Also, the degree of cross-linking constitutes an element of control for the residence time/resorption rate.
In contrast to some of the polymers cited in the above references, dextran employed in the practice of the present invention is available as a USP product and has been used parenterally for many years. Acrylate derivatives of dextran have been produced and can form cross-linked hydrogels (De Groot et al. (2002) Int. J. Cancer, 98, 134-140; Stenekes, et al. (2000) Biomacromolecules, 1, 696-703; Chung, et al. (2005) Int. J. Pharm., 288, 51-61). Polylactide-dextran grafts can be produced and employed to make a delivery matrix using an emulsion based microsphere system (Ouchi, et al. (2004) 4, 458-463)
Commonly owned International Patent Publication No. WO 2004/112713 discloses novel drug polymer complexes, which are formed by mixing a polyanlon such as dextran sulfate sodium and a cationic bioactive agent. The resulting resorbable gels (R Gels) or precipitate constitutes a drug delivery matrix. As disclosed, however, there are only ionic bonds involved in the formation of such R Gels. Furthermore, the formation of such R Gels requires that the active pharmaceutical ingredient must be positively charged. Many active ingredients, however, are neutral or negatively charged at physiological pH. The carbohydrate matrix of R Gels is very attractive in that it is polar and not susceptible to proteolytic degradation.
It would therefore be highly desirable if the resorbable polymer systems were able to deliver neutral or negatively charged active ingredients at physiological pH. It is towards providing such resorbable polymer systems that the present invention is to directed.
Broadly, the present invention disclosed herein entails the usage of chemically modified polysaccharides in the preparation of delivery matrices for drug molecules, which are not usable with conventional R Gels. Included are negatively charged and neutral active ingredients. In especially preferred embodiments, the matrix involves cross-linking of aldehydic polymers with dihydrazides in the presence of an active ingredient. The cross-linking reagent, the dihydrazide, reacts to form a hydrazone. A film, microbeads, or rubbery solid is the product of the reaction.
According to one aspect of this invention, bioerodible compositions for delivery of a bioactive agent are provided which are the reaction products of a reaction mixture comprised of an oxidized dextran solution, and a mixture of solids comprised of a dihydrazide, a bioactive agent, and optionally a pH adjusting agent in an amount sufficient to achieve a pH of the reaction mixture of 6 or less, Preferably the pH of the reaction mixture will be 6 or less whether or not a pH adjusting agent is employed. If employed, however, preferred pH adjusting agents are solid acids, such as sodium phosphate, citric acid, succinic acid and/or fumaric acid.
The compositions of the invention may further comprise a release agent for controlling release of the bioactive agent from the composition. One preferred form of the release agent is a complexing polymer which binds to the bioactive agent. Alternatively or additionally, the release agent may comprise a non-reactive matrix polymer to provide structural stability and diffusional resistance to the bioactive agent. In some preferred embodiments of the invention, the release agent will comprises an aliphatic or aromatic acid which forms salts with aminoglycoside antibiotics, vancomycin, tetracyclines or clindamycin.
Virtually any bioactive agent may be employed satisfactorily in the present invention. In this regard, preferred bioactive agents comprise osteoinductive agents, antibiotics, anesthetics, growth factors, cells, anti-tumor agents, anti-inflammatory agents, antiparasitics, antigens, adjuvants and cytokines. One particularly preferred bioactive agent is an osteoinductive agent, such as demineralized bone matrix (DBM).
The compositions of the invention may be provided in the form of a gel, microsphere, film, foam, or fiber.
According to another aspect of this invention, kits for forming a bioerodible composition adapted for delivery of a bioactive agent are provided. The kits of the invention will comprise a first aliquot portion of a reaction mixture comprised of an oxidized dextran solution, and a second aliquot portion of a reaction mixture comprised of a mixture of solids which include a dihydrazide, a bioactive agent, and optionally a pH adjusting agent in an amount sufficient to achieve a pH of the reaction mixture of 6 or less. When mixed the first and second aliquot portions of the reaction mixture react to form a solidified bioerodible composition for delivery of the bioactive agent contained therein. The release agent, if employed, may therefore be so incorporated into one of the first and second aliquot portions of the reaction mixture.
The kits of the invention may advantageously be provided with a double syringe having first and second syringe barrels which respectively contain the first and second aliquot portions of the reaction mixture.
According to yet another aspect of the invention, methods of making a solidified bioerodible composition for delivery of a bioactive agent are provided. The preferred methods comprise forming a reaction mixture comprised of an oxidized dextran solution, and a mixture of solids comprised of a dihydrazide, a bioactive agent, and optionally a pH adjusting agent in an amount sufficient to achieve a pH of the reaction mixture of 6 or less, and allowing the reaction mixture to react to form a solidified bioerodible drug delivery composition.
Several systems may be employed to prepare the resorbable polymer matrix according to the invention for administration. For example, it is possible to connect two syringes physically one to another and to effect mixing of the reactable components by reciprocating action so as to transfer the mixture repetitively from one syringe barrel to another. The pH is held at 6 or below to prevent reaction of amino groups on the active ingredient. The bioactive agent, dihydrazide, and solid acid (all dry powders) are contained in the first syringe and the oxidized dextran solution in the second syringe. There are many advantages to this format including stability of the bioactive agent, maintenance of sterility, and convenience.
In yet another aspect, the present invention is embodied in implantable medical device which comprises a coating of the solidified bioerodible composition. The medical devices may advantageously be in the form of a catheter, a stent or an orthopedic device. Particularly preferred coated orthopedic devices in accordance with the present invention include pins, screws, rods, nails, wires, augments, cups, and joint implants.
According to yet another aspect of the present invention, methods of delivering a bioactive agent to a body site in need of the same are provided. The methods comprise providing a first aliquot portion of a reaction mixture comprising an oxidized dextran solution, and a second aliquot portion of a reaction mixture comprising a mixture of solids comprised of a dihydrazide, a bioactive agent, and optionally a pH adjusting agent in an amount sufficient to achieve a pH of the reaction mixture of 6 or less. The first and second aliquot portions may be mixed together to form the reaction mixture, so that subsequently, the reaction mixture may be installed at the body site and allowed to form a solidified bioerodible drug delivery composition to be formed thereby in situ. A double syringe having first and second syringe barrels which respectively contain the first and second aliquot portions of the reaction mixture may be provided. The step of expelling the first and second aliquot portions of the reaction mixtures may therefore be practiced by repeatedly transferring the first and second aliquot portions of the reaction mixtures between the first and second syringe barrels so as to mix the same.
These and other aspects and advantages will become more apparent after careful consideration is given to the following detailed description of the preferred exemplary embodiments thereof.